Sustained release, and comfortable opthalmic composition and method for ocular therapy

ABSTRACT

This invention relates to reduced stinging, sustained release ophthalmic formulations and the method of treatment comprising administering such formulations topically to the eye when in need thereof.

This application claim the benefit of U.S. provisional application Ser.No. 60/101,959, filed Sep. 25, 1998

TECHNICAL FIELD

The present invention relates to improved nonstinging, sustained releaseophthalmic formulations for ocular therapy and methods of treatmentcomprising administering such formulations topically to the eye whenindicated.

BACKGROUND ART

Numerous drugs are not readily accepted by many patients because theycause ocular discomfort, i.e., “stinging,” upon instillation to theeyes. This side effect is problematic because it results in poor patientcompliance and because it restricts the amount of drug which can beincluded in topical formulations. Further, to meet USP and globalmicrobiological standards, one or more preservatives must be included inocular formulations. These preservatives, particularly those required tomeet more stringent global requirements, have the tendency to increasethe level of “stinging”, thereby augmenting patient discomfort. Thus,the combined requirements of comfort and satisfactory patient compliancetogether with provision of a composition which meets stringent globalpreservative requirements pose a challenge which, to date, has not beensatisfactorily achieved.

One method for addressing the problems associated with the topicaladministration is described in U.S. Pat. No. 4,911,920. Glaucoma is adisease characterized by an elevated intraocular pressure (IOP)associated with optic nerve head damage and loss of visual field.Statistically, when IOP is lowered, the prognosis for preserving visualfield in an eye with elevated IOP is improved. Thus, a goal of glaucomatherapy is to reduce the IOP to a level within a range tolerated by theeye to slow the progressive loss of visual field. Current medicaltherapy of glaucoma involves the reduction of IOP by various drugs,predominantly ophthalmic beta adrenergic blocking drugs. Betaxolol isamong the ophthalmic beta blockers approved for use to treat glaucoma inthe United States. In the '920 patent, actives such as betaxolol areadministered to treat glaucoma in a composition which includes, interalia, an ion exchange resin and a polyanionic polymer. Thesecompositions have an excellent comfort profile but “stinging” is stillexperienced by some patients.

Thus, there exists a need to provide an ophthalmic composition whichachieves the combined requirements of comfort and satisfactory patientcompliance, while, at the same time, meets stringent global preservativerequirements.

DISCLOSURE OF THE INVENTION

An advantage of the present invention is that it achieves the combinedrequirements of comfort and satisfactory patient compliance, while, atthe same time, meets stringent global preservative requirements, therebypermitting the topical administration of ophthalmic drugs and in higherconcentrations.

Additional advantages and other features of the present invention willbe set forth in part in the description which follows and in part willbecome apparent to those having ordinary skill in the art uponexamination of the following or may be learned from the practice of theinvention. The objects and advantages of the invention may be realizedand obtained as particularly pointed out in the appended claims.

According to the present invention, the foregoing and other advantagesare achieved in part by an ophthalmic composition, comprising: a) atleast one basic active; b) a polyanionic polymer; c) an ion exchangeresin; and d) a pH adjusting agent, wherein said agent is present in anamount sufficient to adjust the pH of the composition to between about3.5 and 9.5.

Another aspect of the present invention is a method of treatment whichcomprises administering topically to an affected eye, an ophthalmiccomposition comprising: a) at least one basic active; b) a polyanionicpolymer; c) an ion exchange resin; and d) a pH adjusting agent, whereinsaid agent is present in an amount sufficient to adjust the pH of thecomposition to between about 3.5 and about 9.5.

Additional objects and advantages of the present invention will becomereadily apparent to those skilled in this art from the followingdetailed description, wherein only the preferred embodiment of theinvention is, shown and described, simply by way of illustration of thebest mode contemplated for carrying out the invention. As will berealized, the invention is capable of other and different embodiments,and its several details are capable of modifications in various obviousrespects, all without departing from the invention. Accordingly, thedrawings and description are to be regarded as illustrative in nature,and not as restrictive.

DESCRIPTION OF THE INVENTION

The present invention is based, in part, on the surprising andunexpected discovery that the use of certain pH adjusting agents, resultin ophthalmic compositions which achieve the combined requirements ofcomfort and satisfactory patient compliance, while, at the same time,meets stringent global preservative requirements.

The pH adjusting agents useful in the present invention may be any“basic amine”, i.e., any amine which shows basicity and does notsubstantially disrupt interaction between a basic active and an ionexchange resin. Preferred pH adjusting agents include ammonia,tromethamine (TRIS or Tris(hydroxymethyl) aminomethane), triethanolamine(TEA), N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES), andmixtures thereof

Disruptions between a basic active and an ion exchange resin normallyoccur when smaller ions such as sodium ions are used to adjust the pH ofthe compositions of concern because they sterically fit better into theresin binding site thereby displacing the basic active from the resinand increasing the concentration of “free” basic active in solution.Since ocular discomfort with many basic actives is proportional to theamount of this “free”, or unassociated basic active present in thecomposition, the level of discomfort experienced by patients increasesas the concentration of unassociated basic active increases. While notwishing to be bound by any particular theory, it is believed that the pHadjusting agents of the present invention minimize disruption of thebasic active/resin interaction as the pH is adjusted which normallyoccurs with smaller ions such as sodium ions. It is believed that thelarger ions provided by the present invention do not fit as well intothe resin binding site and therefore, do not displace as many basicactive molecules.

The term “basic active” as used throughout the specification means theactive ingredient or ingredients in the inventive formulations which maycause ocular discomfort upon instillation to the eye and have thedesired effect and which bear, or are capable of bearing a positivecharge during formulation of the final product or as formulated in thefinal product form. Thus, the term basic, or cationic, active isdescriptive for purposes of the disclosure and claims.

Such basic actives include all ophthalmic agents which can be topicallyapplied. Such ophthalmic agents include, but are not limited to,glaucoma agents, such as beta-blockers, muscarinics, and carbonicanhydrase inhibitors; dopaminergic agonists and antagonists; α-2agonists; anti-infectives; non-steroidal and steroidalanti-inflammatories; prostaglandins; proteins; growth factors andanti-allergics. Compositions of the present invention may also includecombinations of ophthalmic agents.

A preferred basic active is beta blockers which, typically, arerepresented by the following generic structure, which structure alsorepresents the beta blocker basic actives of the present invention:

R¹—O—CH₂—CH(OH)—CH₂—NR²R³  (I)

wherein: R¹ is a substituted or unsubstituted cyclic or aliphaticmoiety; cyclic moieties include mono- and polycyclic structures whichmay contain one or more heteroatoms selected from C, N, and O; R² and R³are independently selected from H and substituted and unsubstitutedalkyl. With regard to Structure (I), above, the following references areincorporated herein by reference: Annual Reports in Medicinal Chemistry14, 81-87 (1979); J. Med. Chem. 1983, 26,1570-1576; ibid. 1984, 27,503-509; ibid. 1983, 26, 7-11; ibid. 1983, 26, 1561-1569; ibid. 19831109-1112; ibid 1983, 26, 950-957; ibid. 1983, 26, 649657; and ibid1983, 26, 352-357. Representative of such basic actives are: betaxolol,timolol, befunolol, labetalol, propranolol, bupranolol, metaprolol,bunalol, esmalol, pindolol, carteolol, hepunolol, metipranolol,celiprolol, azotinolol (S-596), diacetolol acebutolol, salbutamol,atenulol, isoxaprolol, and the like. The following patent publications,which are incorporated herein by reference, further representativelydemonstrate the beta blockers of the present invention: U.S. Pat. Nos.4,252,984; 4,311,708 and 4,342,783.

Preferred beta blockers of the present invention include betaxolol andtimolol. Another preferred basic active is the (S)-isomer of betaxolol,namely, levobetaxolol, the more active of the enantiomers. The inventiveformulations may comprise more than one basic active, such aslevobetaxolol or betaxolol and a carbonic anhydrase inhibitor or aprostaglandin.

In the case where more than one basic active is used in the inventiveformulation, the preferred basic actives include betaxolol orlevobetaxolol with prostaglandin, or a prostaglandin analog, such as,but not limited to, cloprostenol or fluprostenol. More preferably, theprostaglandin includes isopropyl ester of the (+) isomer of fluprostenol(travoprost) having a formula as shown below:

The basic active, in the gel and pourable liquid embodiments, is presentat a level of from about 0.0001 to 5.0 wt. %, the most preferred rangeis from 0.001 to 1.0 wt. %.

As used herein, prostaglandin includes prostaglandin and prostaglandinanalogs thereof, such as, but not limited to, cloprostenol andfluprostenol, as described in U.S. Pat. No. 5,510,383, which isincorporated herein by reference in its entirety to the extent that itdescribes the preparation and known pharmacological profiles ofprostaglandin and prostaglandin analogs, especially cloprostenol,fluprostenol, latanoprost, and travoprost.

The high molecular weight, polyanionic polymers useful in the presentinvention have a molecular weight of from about 50,000 to about 5billion, preferably about 700,000 to about 3 billion. The polymers arecharacterized as having carboxylic acid functional groups, andpreferably contain from 2 to 7 carbon atoms per functional group. Thegels which form during the preparation of the ophthalmic polymerdispersion have a viscosity of from about 3,000 to about 100,000 cps. Inaddition to the basic active-polymer (anionic-cationic) interactions,mentioned above, the high molecular weight polymers used in thecompositions of the present invention thicken the compositions toprovide a gel, and provide a special type of rheology, i.e., plasticviscosity, which is translatable to the sustained release and comfort ofthe final compositions. Such compositions range in pH from 3.0 to 8.5.

The pourable liquid embodiments (administered as drops to the eye) ofthe present invention have a viscosity of from about 1 to 20,000 cps.The pH requirements are the same as recited above for the gel finalproducts, i.e., pH 3.0-8.5.

The third pharmaceutical form of the present invention, the anhydroussalt form, is derived from the free acid or the salt of thepolycarboxylic acid polymer and the basic active. (The presence of thecationic ion exchange resin also contributes to salt formation; thenature of the ion exchange resin, in all embodiments of the presentinvention, is defined below.) Such salts can be formulated, orreconstituted, to aqueous gels and pourable dispersions, as describedabove, on addition of water; or can be formulated as ocular insertsaccording to known technology and shapes; or they can be combined withan oleaginous vehicle to form an ophthalmic ointment. All such finalophthalmic pharmaceutical forms are fully described below.

The term “plastic viscosity”, above, is indicative of a material thatdoes not perceptibly flow until a certain force or stress value isexceeded; this-force or stress is referred to as the yield value. Whilenot wishing to be bound by any theory, it is believed that the increasedduration of activity of the compositions as well as the outstandingsuspension properties of the present invention are related to thepolymer viscoelastic response to shear, i.e., exhibiting a definiteyield value. The compositions of the present invention exhibit a uniqueresponse to shear stress. When the yield value is exceeded, the gelstructure is altered temporarily, allowing the gel to flow. In the eye,this mechanism is partially attributable to the blinking eyelid. Whenthe stress is removed (eyelid at rest), the structure of the gel ispartially reestablished. Other factors which explain the duration of theformulations of the present invention are related to ionic interactions,and a release mechanism which is explained by a dynamic equilibriuminvolving normal tear production and the displacement of basic activecations by cations present in tears.

Suitable polyanionic polymers useful in the present invention arecarboxyl vinyl polymers. Preferred polymers of this class include the socalled Carbomers, available under the trade name Carbopol from the B.F.Goodrich Company; and ethylene maleic anhydride polymeric materialavailable under the trade name EMA from the Monsanto Company. The knownand readily available polymers Carbopol 974 P is specifically preferred.The polymers are used in the aqueous gel compositions at a level up toabout 8% by weight; pourable liquid compositions comprise 0.05% to 2.0%by weight polymer.

The cationic resin component of the formulations of the presentinvention provides an additional means of sustained release of the basicactive, and appears to be necessary for initial and prolonged comfortSuch resins are characterized as either strongly acidic such as thosehaving sulfonic acid functionality, or weakly acidic cation exchangerssuch as those having carboxylic acid functionality. The resin should beincorporated as a finely divided powder, that is, 95% of the resultingspheroidal particles should have a diameter less than 25 microns,preferably 10 or less. The release of the basic active held by thecation exchange resin and the anionic polymer is achieved when ionsnaturally present in the tear fluid, principally sodium and potassium,compete with the bound basic active for sites on the polymer vehicle andthe ion exchange resin. Thus released, the basic active is presented tothe eye surface for transport to the receptor sites.

Any pharmaceutical grade cationic ion exchange resin is suitable for theformulation, an they can be used either in the hydrogen form or in thesodium form. Such resins are readily available, for example, from Rohm &Haas under the “Amberlite” tradename and from Dow Chemical Co. under the“Dowex” tradename. A preferred ion exchange resin is Amberlite® IRP69, across-linked polystyrene sulfonic acid.

The ion exchange resin component is present in the formulations of thepresent invention at a level of from 0.05% to 10.0% by weight. Theaverage particle size diameter of the resin ranges from 1 to 25 micronspreferably 1-10.

The particle size of the resin is important, both with respect to modeof action and comfort. Typically the average particle size of thecommercially available form of the ion exchange material of choice isabout 40 to 150 microns. Such particles are most conveniently reduced toa particle size range of about 1.0 to 25 preferably 1-10 microns by ballmilling, according to known techniques.

The pH adjusting agents are present in an amount sufficient to adjustthe pH of the composition to between about 3.5 and about 9.5,preferably, between about 5 and about 9, more preferably between about 6and 8, and most preferably to a pH of about 6.5. HCl may be optionallyused to adjust the pH in conjunction with the pH adjusting agents of thepresent invention.

Ophthalmic products are typically packaged in unit dose (single dose) ormultidose form. Preservatives are required for multidose packaging toprevent microbial contamination. Suitable preservatives include:benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propylparaben, phenylethyl alcohol, edetate disodium, boric acid, sorbic acid,Onamer M, or other agents known to those skilled in the art. Certainmodified sarcosinates having the following generic structure are alsouseful as preservation potentiators in the present invention:

wherein: R¹═C₄—C₂₇ saturated or unsaturated hydrocarbon:

M═H or a pharmaceutically acceptable salt; and

n=1,2or3.

In general, an amount of one or more sarcosinates of this structure areused in the compositions of the present invention in an amount betweenabout 0.005 and about 0.5 percent by weight (wt %), preferably betweenabout 0.01 and about 0.2 wt %. It is most preferred to use between about0.03 and about 0.12 wt % of one or more of these sarcosinates.

Also preferred are certain lactylates having the following genericstructure:

wherein: R²═C₄—C₂₇ saturated or unsaturated hydrocarbon;

M═H or a pharmaceutically acceptable salt; and

n=1, 2 or 3.

In general, one or more lactylates of this structure may be used in thecompositions in an amount between about 0.1 and about 5.0 wt %. It ispreferred to use an amount between about 0.1 and 2.0 wt %, and it ismost preferred to use about 0.5 wt % of the lactylate.

Preferred surfactants are sold under the Hamposyl® (W. R Grace),Sarkosyl® and Medialan® (Ciba-Geigy) labels. Especially preferred are:lauroyl sarcosine (Hamposyl® L), oleoyl sarcosine (Hamposyl® O),myrstoyl sarcosine (Hamposyl® M), cocoyl sarcosine (Hamposyl® C),stearoyl sarcosine (Hamposyl® S), pelargodoyl sarcosine (Hamposyl® P)and sodium capryl lactylate (Pationic® 122A)

These surfactants can be used in any ophthalmic compositions containingcationic antimicrobials which also contain polyelectrolytes such as highmolecular weight, anionic mucomimetic polymers (e.g., carboxyvinylpolymers such as Carbopol®, polystyrene sulfonic acid polymers, cationicexchange resins (e.g., Amberlite® or Dowex®), or the like. Examples ofsuitable polyelectrolytes are detailed below. Typically suchpreservatives are employed at a level of from 0.001% to 1.0% by weight.

The tonicity, or osmolality, of the product can be adjusted to eitherhypotonicity, isotonicity or hypertonicity relative to normal tears byuse of conventional materials known to the art. Such tonicity agents,however, are limited to nonionic compounds and typically, when employed,range from 0.00% a to 10% weight percent in the final product. Nonionicagents representatively include: mannitol, dextrose, glycerine andpropyleneglycol; their presence in the final product form, however, isoptional.

The ophthalmic formulations of the present invention are in the form of.anhydrous salts; pourable, aqueous dispersions; and aqueous gels. Theformulations comprise, in addition to conventional ingredients whichprovide, for example, bacteriostatic and formulatory balanceconsiderations; a polyanionic vehicle, a cationic exchange resin, andthe basic active of choice. Such anhydrous salt forms are incorporatedinto ointments or solid ocular inserts which form colloidal gels in situon administration to the eye. The pourable liquid and gel embodimentsare applied topically to the eye. It should be noted that such liquidand gel embodiments can be obtained from the anhydrous form onformulation with water.

The formulations of the present invention demonstrate sustained releaseof the basic active and are comfortable on topical administration to theeye. It should be noted, in a general sense, that a stinging sensationresults when the basic actives, identified above, are administered neat.Thus, achieving both comfort and sustained release is an unexpectedresult and permits administration of a class of compounds that otherwisemight not be considered.

The compositions are formulated in three basic states: 1.) gels;2.)pourable liquids, and 3.) anhydrous salts:

1.) Gels: The cationic exchange resin component is dispersed in water.The basic active component is then added with stirring. The polyanionicpolymer component is then added. The resulting product has a viscosityranging from 1000 to 300,000 cps depending on the anionic polymerconcentration. The resulting pH is 3.0 to 8.5, which may be adjusted, ifnecessary, with one of the pH adjusting agents according to theinvention, and optionally, HCl.

2.) Pourable Liquids: The cationic exchange resin component is dispersedin 10 to 50 vol. percent of total water taken in formulation, and thenbasic active is dispersed and/or dissolved with stirrng. The polyanionicpolymer, as an aqueous dispersion, is added until the desired pH of theproduct is obtained. The pH of the product can be adjusted to thedesired value by varying basic active/polymer/resin ratio. The final pHof product can be adjusted with addition of the pH adjusting agentsaccording to the invention, and optionally, HCl. The preferred pH rangefor ophthalmic formulations is from 3.0 to 8.5. The final product is adispersion, which may require high energy mixing to break anyagglomeration to achieve uniformity. Other formulation ingredients arethen added with mixing. The resulting product has a viscosity rangingfrom 1.0 to 20,000 cps depending on the anionic polymer concentration.

3.) Anhydrous Salts: The basic active, the ion exchange resin, and thepolyanionic polymer are combined in water, and following mixing, arelyophilized to a powder. Fillers like mannitol and other materials maybe added to facilitate the freeze/drying processing according totechniques well known to those skilled in the art. The anhydrous saltsproduced in this manner can then be formulated or reconstituted toaqueous gels and liquids, or can be formulated and shaped as ocularinsets. The lyophilized powder can also be combined with a nonaqueousvehicle to form an ophthalmic ointment. Such anhydrous salt embodimentsof the present invention can also be prepared by extracting the initialaqueous dispersion with an organic solvent such as ethanol, chloroform,benzene, or the like, and evaporating the organic solvent to produce thedesired salt complex. The resulting product is substantially equivalentto the above-described lyophilized product.

The ophthalmic formulations of the present invention are administered tothe eyes as gels, pourable liquids (eye drops), and in the form ofointments and ocular inserts; the latter classifications are formulatedform anhydrous salts. All such compositions are formulated to controlthe release of the basic active upon administration to the eye andthereby provide a sustained release effect. Typically suchadministration is necessary one to four times, usually one to two perday. The precise dosage regimen is left to the routine discretion of theclinician.

Compositions according to the present invention are further described asfollows:

Component Specific examples % Active Betaxolol Hydrochloride  0.1-5.0%Viscosity agent Carbopol type polymers,  0.1-1.0% HPMC, HEC, CMC Ionexchange resin Poly[styrene(divyl benzene)  0.1-5.0% sulfonic acidPreservative Benzalkonium chloride, Polyquad 0.002-1.0% Tonicity agentMannitol  1.0-5.0% Preservative aid Boric Acid 0.001-1.0% Chelatingagent Disodium Edetate    0-1.0% Perservative N-lauroylsarcosine   0-1.0% pH adjusting agent Tromethamine to adjust pH, pH adjustingagent Hydrochloric acid to adjust pH Solvent Water qs 100%

While the present invention is disclosed generally above, additionalembodiments are further discussed and illustrated with reference to theexamples below. However, the examples are presented merely to illustratethe invention and are not considered as limitations thereto.

EXAMPLE 1

The compositions shown in Table 1 were prepared as follows: To asolution of levobetaxolol hydrochloride, in purified water was addedpoly (styrene divinylbenzene) sulfonic acid. The suspension was stirredat which time Carbomer 974P slurry, mannitol, boric acid, disodiumedetate and benzalkonium chloride solution were added with continuousstirring. Batch weight was adjusted with purified water and pH wasadjusted to 6.5±0.2 with tromethamine. The suspension was autoclaved andthen sterile filtered, N-lauroylsarcosine was added aseptically.Formulation batch weight was then brought to 100 ml and final pH wasadjusted, as necessary.

TABLE 1 Levobetaxolol Hydrochloride Formulations Concentration 0.25%0.5% 0.75% Ingredient Percent w/v Percent w/v Percent w/v Levobetaxoiol0.28^(a) 0.56^(b) 0.84^(c) hydrochloride Poly(styrene 0.375 0.75 1.125divinylbenzene) Sulfonic Acid Carbomer 974 P 0.35 0.35 0.35 Mannitol 4.54.0 3.67 Boric Acid 0.3 0.3 0.3 Disodium Edetate 0.01 0.01 0.01Benzalkonium 0.01 + 0.01 + 0.01 + Chloride 5% excess^(d) 5% excess^(d)5% excess^(d) N-Lauroylsarcosine 0.03 0.03 0.03 Tromethamine pH adjustto 6.5 pH adjust to 6.5 ± 0.2 Hydrochloric Acid 6.5 ± 0.2 6.5 ± 0.2 6.5± 0.2 (if needed) Purified Water QS 100% QS 100% QS 100% ^(a)Equivalentto 0.25% betaxolol free base ^(b)Equivalent to 0.5% betaxolol free base^(c)Equivalent to 0.75% betaxolol free base ^(d)The 5% excess is addedas a development overage

EXAMPLE 2

The results in Table 2 demonstrate that there is an increased boundfraction of betaxolol when TRIS or triethanolamine are utilized toadjust the pH of Betoptic S as measured by HPLC.

TABLE 2 Influence of several pH adjusting bases on bound betaxol insuspension pH Adjusting Base % Bound Betaxolol NaOH (Control) 56 TRIS 63TEA 59 Na HEPES 53

EXAMPLE 3

The results in Table 3 summarize work done with TRIS vs. NaOH andconfirm that the use of TRIS as a pH adjusting agent increases thefraction of betaxolol bound to the resin which in turn increasescomfort.

TABLE 3 Components 1 2 3 4 5 6 7 8* Betopic-S* (S) Betaxolol HCl, 0.56%0.56% 0.56% 0.56% 0.56% 0.56% 0.56% 0.28% 0.28% USP Amberlite IRP-69,0.75% 0.75% 0.75% 0.75% 1.00% 0.75% 0.75% 0.25% 0.25% NOC Carbomer 974P0.40% 0.40% 0.40% 0.40% 0.40% 0.40% 0.40% 0.45% 0.20%** (934P) Mannitol,USP 3.75% 3.75% 3.75% 3.75% 3.75% 3.75% 3.75% 4.8% 4.5% Boric acid, NF0.30% 0.30% 0.40% 0.40% 0.40% 0.40% 0.40% 0.4% 0 Disodium EDTA, 0.01%0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% USP Benzalkonium 0.01% +5% 0.01% + 5% 0.01% + 5% 0.01% + 5% 0.01% + 5% 0.01% + 5% 0.01% + 5%0.01% + 5% 0.01% + 5% Chloride, NF xs xs xs xs xs xs xs xs xsN-Lauroylsarcosine, 0.03% 0.03% 0.03% 0.03% 0.03% 0.03% 0.03% 0.03% 0NOC Tromethamine, AR 25 ml — 30 ml — — 32.5 ml — 10% Stock NaOH — 6N,3.3 ml — 6N, 4.1 ml 6.25N, — 6.25N, NaOH NaoH 2.85 ml 2.9 ml PurifiedWater, OSP 100% 100% 100% 100% 100% 100% 100% 100% 100% Batch Size Made200 gm 200 gm 200 gm 200 gm 200 gm 200 gm 200 gm pH 6.5 6.5 6.6 7.0 7.07.0 7.0 7.0 7.6 % Total Betaxolol 99.86% 102.82% 99.66% 108.92% 98.11%104.23% 98.41% 98%, 99% 95-105 % Free Betaxolol 20.50% 24.55% 21.13%27.70% 21.61% 23.11% 28.23% 45, 46 5%-25% Viscosity @ 1.5 382, 379 301,294 250, 281 259, 282 111, 109 235, 254 76.8, 79.5 260 NMT 350 @ RPM; CP42 (50-100) 1.5 pm Osmolaritry 283 284 287 307 273 307 290 312 270-300*R.S.-Betaxolol HCl **Carbomer 934P

EXAMPLE 4

The results in Table 4 summarize work done with TRIS vs. NaOH andconfirm that the use of TRIS as a pH adjusting agent increases thefraction of betaxolol bound to the resin. These results further confirmthat the inclusion of TRIS does not modify the preservative propertiesof the formulations.

TABLE 4 PET and comfort results of initial three formulation of 0.50%(S)Betaxolol Suspension Formualtion Betoptic ® Components 1 3 4 8 S (S)Betaxolol, HCL, USP 0.56% 0.56% 0.56% 0.28%* 0.28%* Amberlite IRP-69,NOC 0.75% 0.75% 0.75% 0.25% 0.25% Carbomer 974P 0.40% 0.40% 0.40% 0.45%0.20% (934P) Mannitol, USP 3.75% 3.75% 3.75% 4.8% 4.5% Boric acid, NF0.30% 0.40% 0.40% 0.4% 0 Disodium EDTA, USP 0.01% 0.01% 0.01% 0.01%N-lauryl sarosine 0.03 0.03 0.03 0.03 0 Benzalkonium Chloride, NF0.01% + 5% xs 0.01% + 5% xs 0.01% + 5% 0.01% + 5% 0.01% + xs xs 5% xsTromethamine, AR 10% 25 ml 30 ml — — Stock NaOH — — 6N, 4.1 ml NaOH NaoHPurified Water, USP 100% 100% 100% 100% 100% Batch Size Made 200 gm 200gm 200 gm — — pH 6.5 6.6 6.5 7.0 7.6 PET Results Pass USP Pass USP PassUSP Pass USP Pass USP Pass Ph. Eur. B Pass Ph. Eur. B Pass Ph. Pass Ph.Eur. A Eur. B *Racemic R.S. betazolol HCl

In the previous descriptions, numerous specific details are set forth,such as specific materials, structures, chemicals, processes, etc., inorder to provide a thorough understanding of the present invention.However, the present invention can be practiced without resorting to thedetails specifically set forth. In other instances, well knownprocessing structures have not been described in detail in order not tounnecessarily obscure the present invention.

EXAMPLE 5

Tables 5, 6, and 7 summarize preferred formulations of the invention.

TABLE 5 BRINZOLAMIDE/LEVOBETAXOLOL OPTHALMIC SUSPENSION COMPONENTPERCENT W/V % Levobetaxolol Hydrochloride 0.56^(a) Brinzolamide 1 + 2%excess Amberlite IRP-69 0.75 Carbopol 974P 0.3 Mannitol 4.0 Boric Acid0.4 Disodium Edetate 0.01 Tyloxapol 0.025 N-lauroylsarcosine 0.03Benzalkomium Chloride 0.01 Tromethamine QS pH 6.5 ± 0.2 Purified WaterQS 100 ^(a)Equivalent to 0.5 betaxolol base

TABLE 6 FORMULAS COMPONENT 9 10 11 12 13 14 15 Fluprostenol isopropylester 0.004 0.004 0.004 0.004 0.004 0.004 0.004 LevobetaxololHydrochloride 0.56 0.56 0.56 0.56 0.56 0.56 0.56 HCO-40 0.5 0.5 0.5 0.50.5 0.5 0.5 Amberlite IRP-69 1.0 0.75 1.0 1.0 1.0 0.75 0.75 Poly(styrene divinylbenzene) Sulfonic Acid Carbopol 974P 0.35 0.2 0.35 0.350.35 0.35 0.35 Glycerine — 1.8 — — — 1.0 — Mannitol 3.5 — 3.3 3.3 3.3 —3.3 Boric Acid 0.3 0.35 0.3 0.3 0.3 0.3 0.3 Disodium Edetate 0.01 0.010.01 0.01 0.01 0.01 0.01 Benzalkonium Chloride 0.015 0.01 0.015 0.015 —0.01 0.01 N-lauroylsarcosine 0.05 0.05 0.05 0.04 0.05 0.05 0.05Tyloxapol — 0.025 — — — — — Tromethamine 0.12 Adjust pH Adjust pH AdjustpH Adjust pH Adjust pH Adjust pH 6.0 6.0 ± 0.2 6.0 ± 0.2 6.0 ± 0.2 6.0 ±0.2 6.0 ± 0.2 6.0 ± 0.2 Hydrochloric Acid Adjust pH Adjust pH Adjust pHAdjust pH Adjust pH Adjust pH Adjust pH 6.0 6.0 ± 0.2 6.0 ± 0.2 6.0 ±0.2 6.0 ± 0.2 6.0 ± 0.2 6.0 ± 0.2 6.0 ± 0.2 Purified Water QS 100% QS100% QS 100% QS 100% QS 100% QS 100% QS 100%

TABLE 7 FORMULAS COMPONENT 16 17 18 19 Fluprostenol isopropyl 0.0040.004 0.004 0.004 ester Betaxolol (R,S) 0.56 0.56 0.56 0.28Hydrochloride HCO-40 0.5 0.5 0.5 0.5 Amberlite IRP -69 1.0 0.75 0.750.375 Poly (styrene divinylbenzene) Sulfonic Acid Carbopol 974P 0.350.35 0.35 0.35 Mannitol 3.5 3.3 3.3 3.5 Boric Acid 0.3 0.35 0.3 0.3Disodium Edetate 0.01 0.01 0.01 0.1 Benzalkonium Chloride 0.015 0.0150.015 0.01 N-Lauroylsarcosine 0.05 0.05 0.05 0.05 Tromethamine Adjust pHto 6.3 ± 0.2 Adjust pH to 6.0 ± 0.2 Adjust pH to 6.5 ± 0.2 Adjust pH to6.0 ± 0.2 Hydrochloric Acid Adjust pH to 6.3 ± 0.2 Adjust pH to 6.0 ±0.2 Adjust pH to 6.5 ± 0.2 Adjust pH to 6.0 ± 0.2 Sodium Hydroxide — — —— Purified Water QS 100% QS 100% QS 100% QS 100%

Only the preferred embodiment of the invention and an example of itsversatility are shown and described in the present disclosure. It is tobe understood that the invention is capable of use in various othercombinations and environments and is capable of changes or modificationswithin the scope of the inventive concept as expressed herein.

What is claimed is:
 1. An ophthalmic composition, comprising: a) atleast one basic active; b) a polyanionic polymer; c) an ion exchangeresin; and d) a pH adjusting agent, wherein said agent is present in anamount sufficient to adjust the pH of the composition to between about3.5 and about 9.5 and wherein the pH adjusting agent is a basic amineand does not substantially disrupt interaction between the basic activeand the ion exchange resin.
 2. The composition according to claim 1,wherein the basic active is selected from the group consisting ofglaucoma agents, muscarinics, carbonic anhydrase inhibitors,dopaminergic agonists and antagonists, post surgical α-2 agonists,anti-infectives, non-steroidal and steroidal anti-inflammatories,prostaglandins, proteins, growth factors, anti-allergics, beta blockers,and mixtures thereof.
 3. The composition according to claim 2, whereinthe basic active is a beta blocker.
 4. The composition according toclaim 3, wherein the beta blocker is levobetaxolol.
 5. The compositionaccording to claim 3, wherein the beta blocker is present at aconcentration between about 0.1% and about 5.0%.
 6. The compositionaccording to claim 1, wherein the pH adjusting agent is selected fromthe group consisting of ammonia, tromethamine (TRIS orTris(hydroxymethyl)aminomethan), triethanolamine (TEA), N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES), and mixtures thereof. 7.The composition according to claim 1, wherein the pH adjusting agentfurther comprises hydrochloric acid.
 8. The composition according toclaim 1, wherein said pH adjusting agent is present in an amountsufficient to adjust the pH of the composition to between about 5 andabout
 9. 9. The composition according to claim 8, wherein said pHadjusting agent is present in an amount sufficient to adjust the pH ofthe composition to between about 6 and about
 8. 10. The compositionaccording to claim 9, wherein said pH adjusting agent is present in anamount sufficient to adjust the pH of the composition to about 6.5. 11.The composition according to claim 1, wherein the composition is in theform of an aqueous gel, a pourable aqueous dispersion, or an anhydroussalt.
 12. The composition according to claim 1, further comprising oneor more preservatives.
 13. The composition according to claim 1, furthercomprising one or more tonicity agents.
 14. An opthalmic compositioncomprising: levobetaxolol hydrochloride; poly(styrene divinylbenzene)sulfonic acid; carbomer; mannitol; boric acid; disodium edetate;benzalkonium chloride; N-lauroylsarcosine; and tromethamine, andoptionally hydrochloric acid, in an amount sufficient to adjust the pHof the composition to between about 6.5.
 15. The composition accordingto claim 1, wherein said basic active comprises betaxolol, andprostaglandin or prostaglandin analog.
 16. The composition according toclaim 15, wherein said betaxolol is levobetaxolol, and saidprostaglandin analog is cloprostenol, fluprostenol, latanoprost, ortravoprost.
 17. The composition according to claim 15, wherein saidprostaglandin analog is travoprost.
 18. A method of treating an eye inneed thereof, which comprises administering topically to an affectedeye, an ophthalmic composition comprising: a) at least one basic active;b) a polyanionic polymer; c) an ion exchange resin; and d) a pHadjusting agent, wherein said agent is present in amount sufficient toadjust the pH of the composition to between about 3.5 and about 9.5; andwherein the pH adjusting agent is a basic amine and does notsubstantially disrupt interaction between the basic active and the ionexchange resin.
 19. The method according to claim 18, wherein the basicactive is selected from the group consisting of glaucoma agents,muscarinics, carbonic anhydrase inhibitors, dopaminergic agonists andantagonists, post surgical α-2 agonists, anti-infectives, non-steroidaland steroidal anti-inflammatories, prostaglandins, proteins, growthfactors, anti-allergics, beta blockers and mixtures thereof.
 20. Themethod according to claim 1, wherein the basic active is a beta blocker.21. The method according to claim 20, wherein the beta blocker islevobetaxolol.
 22. The method according to claim 20, wherein the betablocker is present at a concentration between about 0.1% and about 5.0%.23. The method according to claim 19, wherein the pH adjusting agent isselected from the group consisting of ammonia, tromethamine (TRIS orTris(hydroxymethyl)aminomethan), triethanolamine (TEA),N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid), (HEPES), andmixtures thereof.
 24. The method according to claim 18, wherein the pHadjusting agent further comprises hydrochloric acid.
 25. The methodaccording to claim 18, wherein said pH adjusting agent is present in anamount sufficient to adjust the pH of the composition to between about 5and about
 9. 26. The method according to claim 25, wherein said pHadjusting agent is present in an amount sufficient to adjust the pH ofthe composition to between about 6 and about
 8. 27. The method accordingto claim 26, wherein said pH adjusting agent is present in an amountsufficient to adjust the pH of the composition to about 6.5.
 28. Themethod according to claim 19, wherein the composition is in the form ofan aqueous gel, a pourable aqueous dispersion, or an anhydrous salt. 29.The method according to claim 19, further comprising one or morepreservatives.
 30. The method according to claim 19, farther comprisingone or more tonicity agents.
 31. The method according to claim 19,wherein said basic active comprises betaxolol, and prostaglandin orprostaglandin analog.
 32. The method according to claim 33, wherein saidbetaxolol is levobetaxolol, and said prostaglandin analog iscloprostenol, fluprostenol, latanoprost, or travoprost.
 33. Thecomposition according to claim 33, wherein said prostaglandin analog istravoprost.